Project Summary/Abstract This application addresses Grand Opportunity: Phase 2 Clinical Trials Program of Novel Therapies for HLB Diseases. Obstructive sleep apnea (OSA) afflicts >5% of adults and is associated with a 2 to 4-fold increased risk of cardiovascular disease (CVD). Despite the availability of positive airway pressure (PAP) therapy, which effectively relieves airway obstruction, most OSA patients remain untreated, and thus at increased CVD risk. Suboptimal case-identification and treatment of patients with OSA is, in part, from the complexity of diagnostic algorithms and the perceived burden of using a nightly appliance, which in some individuals results in discomfort and sleep disruption. Thus, there is a need to develop and test alternative approaches to OSA treatment that address CVD risk. Emerging data indicate the central role of intermittent hypoxemia as a key mediator of pro-inflammatory, pro-oxidative and metabolic dysregulatory responses to OSA. There is thus a strong scientific basis for rigorously evaluating the efficacy of a relatively simple therapy, nocturnal supplemental oxygen (NSO), on intermediate markers of CVD risk. In this Phase 2 randomized controlled trial, we will capitalize on an existing collaborative research team (Sleep Heart Health Study investigators) experienced with the conduct of multicenter studies of OSA, expanding the team to include experienced cardiovascular translational and clinical trials investigators, to evaluate the novel use of NSO in the treatment of patients with OSA at high risk for CVD events. A pathways-directed outcomes assessment will be conducted to identify the reversibility of putative pro-inflammatory, pro-oxidative, and vascular responses to OSA. Outcomes will include critical mediators of hypoxemia effects, as well as changes in patient-reported outcomes, such as quality of life. Performing a head-to-head comparison of PAP and NSO, we will recruit 1400 patients at high risk for CVD events without significant sleepiness from 4 cardiology practice sites to undergo home sleep monitoring. We will randomize 354 of these patients with moderate to severe OSA to one of three treatment arms: a) optimized medical therapy for prevention of CVD events;b) optimized medical therapy plus PAP;or c) optimized medical therapy plus NSO. Participants will be evaluated with monthly telephone assessments and a 3-month follow-up visit, evaluating adherence, changes in OSA severity, quality of life/sleepiness, and a targeted group of intermediate CVD risk factors chosen for their predictive value for CVD and/or their sensitivity to hypoxemia. These include: 24 hour blood pressure;biochemical indices of CVD risk;sympathetic activity;and overnight indices of cardiac electrophysiologic activity. These coordinated efforts of leading institutions will accelerate the ability to conduct a large-scale Phase 3 clinical trial by assembling a multidisciplinary, multi-institutional team;establishing key study cores and infrastructure;refining recruitment, retention and measurement procedures;identifying key intermediate study endpoints;and establishing the safety and efficacy of the novel intervention (NSO) in OSA patients. (End of Abstract)